Currently, the standard of care for the systemic treatment of breast cancer involves treatment with anthracyclines and taxanes. The use of the anthracyclines and taxanes is increasing and more patients are developing resistance to these agents.

Prior studies have shown that capecitabine is an effective agent after patients have failed anthracyline and taxane regiments.

Newer agents are needed to treat breast cancer which has become refractory to anthracyclines and taxanes. Epothilones are a new class of chemotherapeutics which have been demonstrated to have synergistic activity with capecitabine in preclinical tumor models. Epothilones have been shown to have activity in multi-drug resistant cancers and prior phase I/II studies have suggested that it is safe and efficacious. Prior Phase II studies have demonstrated response rates of 12-41%.

In the present study a member of the epothilones family, ixabepilone, was studied. It was combined with capecitabine treatment and was compared with capecitabine treatment alone.

Materials and Methods

The present study is a Phase III, randomized, open label, multi-institutional trial comparing combined treatment with capecitabine and ixabepilone with capecitabine alone in patients with metastatic breast cancer who have failed previous chemotherapy.

The primary endpoint of this study was progression free survival (PFS).

In the combined treatment group ixabepilone was administered on the first day of each three week cycle to a dose of 40 mg/m2 IV over three hours. 1000 mg/ m2 of capecitabine was administered twice a day by mouth for the first 14 days of each three week cycle.

In the capecitabine alone arm, 1250 mg/ m2 of capecitabine was administered twice a day by mouth for the first 14 days of each three week cycle.

Failure was defined as:

In patients who received anthracyclins or taxanes for recurrence:

Progression while on anthracycline therapy within the last 3 months.

Progression while on taxane therapy within the last 4 months.

In patients who received anthracyclins or taxanes as adjuvant therapy:

Progression while on anthracycline therapy in the last 6 months.

Progression while on taxane therapy in the last 12 months.

Additionally, if patients had progressed after receiving the maximum dose of doxyrubicin or epirubicin they were considered as having failed.

Exclusion Criteria:

Patients who had failed more than three previous chemotherapy treatments, including adjuvant treatment, were excluded.

Patients with grade II peripheral neuropathy were excluded.

Patients with grade II liver function test abnormalities were excluded. Initially there was an exception to this for patients with liver metastasis. However, due to increased toxicity during interim analysis, all patients with grade II hepatic toxicity were excluded.

Response and progression were monitored for radiologically by both an independent review committee and the investigators.

Statistical analysis demonstrated that 615 events would be needed to detect a hazard ration of 0.77 with a 90% power and a p-value of 0.05.

Results

A total of 752 patients were randomized over the course of two and a half years. The patient characteristics between the two groups were well balanced.

The cohort of patients was heavily pretreated prior to entering the study.

48% of patients had received one prior metastatic regimen and 43% had received two.

The median number of cycles completed by patients in the combined treatment arm was five. For patients in the capecitabine arm it was four cycles.

Patients who received combined treatment with ixabepilone and capecitabine had a significant improvement in PFS compared with patients treated with capecitabine alone.

The hazard ration for PFS comparing the combined treatment arm with the capecitabine alone arm was 0.75.

PFS based on the independent review committee's evaluation was 5.8 and 4.2 months for the combined treatment and capecitabine alone arms, respectively (p=0.0003).

PFS based on the investigators' evaluation was 5.3 and 3.8 months for the combined treatment and capecitabine alone arms, respectively (p=0.0011)

12 week PFS percentage was 71% in the combined treatment arm and 55% in the capecitabine alone arm (p<0.0001).

Benefit was seen across almost all groups of patients and included patients who were triple negative and Her2 positive.

The objective response rate based on evaluation by the independent review committee was 35% and 14% for the combined treatment arm and capecitabine alone arm, respectively.

Toxicity:

There was no significant increase in diarrhea or mucositis in the combined treatment arm compared with the capecitabine alone arm.

Grade 3 or 4 neuropathy occurred in 23% of patients in the combined treatment arm compared with 0% in the capecitabine alone arm. Neuropathy was primarily sensory, cumulative and generally reversible over a six week time period.

Hand foot syndrome occurred in 18% of patients in the combined treatment arm and 17% of the capecitabine alone arm

Fatigue occurred in 9% of patients in the combined treatment arm and 3% of the capecitabine alone arm.

There was an approximately 2.5 fold increase in objective response rates with combined treatment across almost all groups.

Ixabepilone appears to be safe in patients with normal liver function.

Survival data is pending.

Clinical/Scientific Implications

As greater numbers of breast cancer patients are treated with anthracyclin and taxane based chemotherapy for breast cancer, newer second line treatments are needed to treat patients who will eventually fail these regimens. This Phase III randomized clinical trial suggests that the combined use of ixabepilone and capecitabine is effective in prolonging PFS compared with capecitabine alone.

Ixabepilone combined with capecitabine did not worsen the mucositis and diarrhea commonly associated with capecitabine use and the combination was generally well tolerated. The data suggests that this combination is safe when patients without liver dysfunction are excluded.

Ixabeilone were originally isolated from the African myxobacteria species known as Sorangium cellulosum. Prior studies have shown that the rate of neurotoxicity in patients with metastatic breast cancer treated with ixabepilone alone are about 3% and that generally other side effects, such as nausea are less frequent compared with paclitaxel treatment.

However, as the overall survival results are still pending, it is not clear that this combination of chemotherapies is of benefit to patients. It is possible that radiologically, there is improvement in the tumor burden without an improvement in overall survival. Hence, these results show potential for the use of ixabeilone with capecitabine in metastatic breast cancer; however more data is necessary at this point.